Abstract

Nervous system injury is a frequent result of cancer therapy involving cranial irradiation, leaving patients with marked memory and other neurobehavioral disabilities. Here, we report an unanticipated link between bone marrow and brain in the setting of radiation injury. Specifically, we demonstrate that bone marrow-derived monocytes and macrophages are essential for structural and functional repair mechanisms, including regeneration of cerebral white matter and improvement in neurocognitive function. Using a granulocyte-colony stimulating factor (G-CSF) receptor knockout mouse model in combination with bone marrow cell transplantation, MRI, and neurocognitive functional assessments, we demonstrate that bone marrow-derived G-CSF-responsive cells home to the injured brain and are critical for altering neural progenitor cells and brain repair. Additionally, compared with untreated animals, animals that received G-CSF following radiation injury exhibited enhanced functional brain repair. Together, these results demonstrate that, in addition to its known role in defense and debris removal, the hematopoietic system provides critical regenerative drive to the brain that can be modulated by clinically available agents.

(A) Schematic diagram of the experimental layout. Mice were treated with whole-body irradiation (9.5 Gy) and transplanted the next day with either WT or G-CSFR–/– bone marrow cells. After reconstitution of the blood (), mice underwent focal brain irradiation (4.5 Gy) followed by G-CSF treatment on days 1, 3, 5, 7, 14, and 21 after irradiation. BrdU was injected on days 21, 28, and 47 after irradiation. Mice were sacrificed on day 47, 4 hours after the last BrdU injection. (B) Quantification of BrdU+ progenitors in the cerebral white matter and germinal zones of the brain. Asterisks indicate a significant change relative to control. *P < 0.05; ****P < 0.0001, 1-way ANOVA. n = 6 independent biological replicates. Data are presented as mean ± SEM of biological replicates.

focal-brain irradiation. Mice were exposed to either whole-body (4.5 Gy) or focal-brain irradiation (3 × 2 Gy) or left untreated. On the next day, mice were treated by vehicle control or G-CSF (on days 1–5) and subsequently were treated weekly until sacrifice at day 35 after irradiation. All mice were injected with BrdU on days 1–5. Original magnification: ×10. (A) Immunohistochemical assessment of BrdU-positive (red) and NeuN-positive (green) cells in the SVZ, DG, and CC. (B) Quantification of BrdU+ and NeuN+ cells. Asterisks indicate a significant change relative to control. *P < 0.05; **P < 0.01; ****P < 0.0001, 1-way ANOVA. n = 3 independent biological replicates. Data are presented as mean ± SEM of biological replicates.